This invention relates to a spray drying process for forming pharmaceutical compositions comprising a solid amorphous dispersion of a low-solubility drug and a polymer.
It is sometimes desired to form a solid amorphous dispersion of a drug and a polymer. One reason for forming solid amorphous dispersions is that the aqueous dissolved drug concentration of a poorly aqueous soluble drug may be improved by forming an amorphous dispersion of the drug and a polymer. For example, Curatolo et al., EP 0 901 786 A2 disclose forming pharmaceutical spray-dried dispersions of sparingly soluble drugs and the polymer hydroxypropyl methyl cellulose acetate succinate. Such solid amorphous dispersions of drug and polymer provide higher concentrations of dissolved drug in an aqueous solution compared with the drug in crystalline form. Such solid amorphous dispersions tend to perform best when the drug is homogeneously dispersed throughout the polymer.
While spray drying processes are well known, spray drying solid amorphous dispersions provides a number of unique challenges. Spray drying involves dissolving the drug and polymer in a solvent to form a spray solution, atomizing the spray solution to form droplets, and then rapidly evaporating the solvent from the droplets to form the solid amorphous dispersion in the form of small particles. The solid amorphous dispersion particles are preferably homogeneous, solid dispersions of amorphous drug in the polymer. Often, it is desirable for the amount of drug in the solid amorphous dispersion to be greater than the solubility of the drug in the polymer (in the absence of the solvent), while still having the drug homogeneously dispersed in the polymer rather than separated into drug-rich domains. Such homogeneous solid amorphous dispersions are termed “thermodynamically unstable.” To form such dispersions by spray drying, the solvent must be evaporated rapidly from the spray solution droplets, thereby achieving a homogeneous solid amorphous dispersion. However, rapid evaporation of solvent tends to lead to particles that are either very small, have very low density (high specific volume), or both. Such particle properties can lead to difficulties handling the material and formation of dosage forms containing the solid amorphous dispersion particles.
In contrast, drying conditions that tend to favor larger, denser particles may result in other problems. First, slow evaporation of the solvent from the spray solution droplets may allow the drug to separate from the polymer during evaporation of the droplets, leading to non-homogeneous, phase-separated dispersions. That is, the solid dispersion contains a drug-rich phase and a polymer-rich phase. Second, drying conditions that favor large, dense particles can result in high levels of residual solvent in the solid amorphous dispersion. This is undesirable for at least two reasons. First, high residual solvent levels in the solid amorphous dispersion particles can result in non-homogeneous dispersions in which the drug phase separates from the polymer. Second, as the amount of residual solvent increases, the product yield from spray drying decreases due to incomplete drying of the droplets, which allows the damp droplets to stick to various portions of the dryer. Polymer and drug that stick to the dryer surfaces not only lowers yields, but can break loose from the surface and be present in the product as large, non-homogeneous particles or chunks. Such material often has higher levels of impurities if the material is exposed to high temperatures for longer times than the majority of the spray dried material.
In addition, the production of large quantities of solid amorphous dispersion particles for commercial purposes requires that large volumes of solvent must be used. The process used to spray dry large quantities of spray solution must be capable of balancing the need to rapidly evaporate solvent to form homogeneous solid amorphous dispersions with the need to form particles that have the desired levels of residual solvent and handling characteristics.
Finally, it is often desirable to utilize a drying gas such as nitrogen that is inert and reduces the potential for fire or explosions. It is desirable to minimize the use of such gases due to cost as well as minimize the amount of solvent discharged as vapor in such gases following use.
Accordingly, there is still a need for a spray drying process to prepare pharmaceutical compositions of solid amorphous dispersions comprising low-solubility drugs and polymers that is capable of providing large quantities of spray dried solid amorphous dispersions that are homogeneous, are dense, and have low residual solvent content.